Thioester prodrugs of macrocycles as inhibitors of histone deacetylases

Abstract

The present invention provides a novel macrocyclic prodrug compound of general Formula (I), a pharmaceutical composition comprising a compound of Formula (I), and a method for treating diseases mediated by HDAC enzymes by administering a compound of Formula (I), wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , A and Z are defined herein.

1 .- 17 . (canceled) 
     
     
         18 . A method for preparing a thiol compound of formula 6 
       
         
           
           
               
               
           
         
         comprising reacting a chloride compound of formula 1 
       
       
         
           
           
               
               
           
         
         with a thioacid, 
         followed by hydrolysis of the resulting thioester with a reducing agent to provide the compound of formula 6. 
       
     
     
         19 . The method according to  claim 18 , wherein the thioacid is a compound of formula 2 
       
         
           
           
               
               
           
         
         wherein:
 Ra is Boc; 
 Rb is H; 
 Rx is H or lower alkyl; and 
 Ry is H or lower alkyl. 
 
       
     
     
         20 . The method according to  claim 18 , wherein the reducing agent is hydrazine hydrate. 
     
     
         21 . A method for preparing a compound of formula 4 
       
         
           
           
               
               
           
         
         wherein:
 Ra and Rb are H; 
 Rx is H or lower alkyl; and 
 Ry is H or lower alkyl, 
 
         the method comprising reacting a chloride compound 1 
       
       
         
           
           
               
               
           
         
         with a thioacid of formula 2 
       
       
         
           
           
               
               
           
         
         to provide a compound of formula 3 
       
       
         
           
           
               
               
           
         
         wherein:
 Ra is Boc; 
 Rb is H; 
 Rx is H or lower alkyl; and 
 Ry is H or lower alkyl, 
 
         followed by deprotection of the compound of formula 3 to provide the compound of formula 4. 
       
     
     
         22 . The method according to  claim 21 , further comprising treating the compound of formula 4 with an acid HX to form a compound of formula 5 
       
         
           
           
               
               
           
         
         wherein:
 Ra and Rb are H; 
 Rx is H or lower alkyl; and 
 Ry is H or lower alkyl. 
 
       
     
     
         23 . The method according to  claim 21 , wherein the chloride compound of formula 1 is reacted with the thioacid of formula 2 in the presence of a base. 
     
     
         24 . The method according to  claim 21 , wherein the chloride compound of formula 1 is reacted with the thioacid of formula 2 in the presence of a base and an iodide salt. 
     
     
         25 . The method according to  claim 23 , wherein the base is potassium carbonate. 
     
     
         26 . The method according to  claim 21 , wherein the compound of formula 3 is deprotected to the compound of formula 4 by treatment with trifluoroacetic acid. 
     
     
         27 . The method according to  claim 22 , wherein the acid HX is selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, fumaric acid, maleic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, methanesulfonic acid, benzenesulfonic acid, 4-nitrobenzene sulfonic acid, 4-bromobenzene sulfonic acid, toluensulfonic acid, naphthalene sulfonic acid, naphthalene disulfonic acid, and polygalacturonic acid. 
     
     
         28 . The method according to  claim 21 , wherein the compound of formula 3 is selected from the group consisting of:
 (R)-S-((E)-4-((7S,10S)-7-isopropyl-4,4-dimethyl-2,5,8,12-tetraoxo-9-oxa-16-thia-3,6,13,18-tetraazabicyclo[13.2.1]octadeca-1(17),15(18)-dien-10-yl)but-3-en-1-yl)-2-((tert-butoxycarbonyl)amino)-3-methylbutanethioate;   (S)-S-((E)-4-((7S,10S)-7-isopropyl-4,4-dimethyl-2,5,8,12-tetraoxo-9-oxa-16-thia-3,6,13,18-tetraazabicyclo[13.2.1]octadeca-1(17),15(18)-dien-10-yl)but-3-en-1-yl)-2-((tert-butoxycarbonyl)amino)-3-methylbutanethioate;   (S)-S-((E)-4-((7S,10S)-7-isopropyl-4,4-dimethyl-2,5,8,12-tetraoxo-9-oxa-16-thia-3,6,13,18-tetraazabicyclo[13.2.1]octadeca-1(17),15(18)-dien-10-yl)but-3-en-1-yl)-2-((tert-butoxycarbonyl)amino)propanethioate; and   (R)-S-((E)-4-((7S,10S)-7-isopropyl-4,4-dimethyl-2,5,8,12-tetraoxo-9-oxa-16-thia-3,6,13,18-tetraazabicyclo[13.2.1]octadeca-1(17),15(18)-dien-10-yl)but-3-en-1-yl)-2-((tert-butoxycarbonyl)amino)propanethioate.   
     
     
         29 . The method according to  claim 22 , wherein compound of formula 5 is selected from the group consisting of:
 (R)-S-((E)-4-((7S,10S)-7-isopropyl-4,4-dimethyl-2,5,8,12-tetraoxo-9-oxa-16-thia-3,6,13,18-tetraazabicyclo[13.2.1]octadeca-1(17),15(18)-dien-10-yl)but-3-en-1-yl)-2-amino-3-methylbutanethioate hydrochloride;   (S)-S-((E)-4-((7S,10S)-7-isopropyl-4,4-dimethyl-2,5,8,12-tetraoxo-9-oxa-16-thia-3,6,13,18-tetraazabicyclo[13.2.1]octadeca-1(17),15(18)-dien-10-yl)but-3-en-1-yl)-2-amino-3-methylbutanethioate hydrochloride;   (S)-S-((E)-4-((7S,10S)-7-isopropyl-4,4-dimethyl-2,5,8,12-tetraoxo-9-oxa-16-thia-3,6,13,18-tetraazabicyclo[13.2.1]octadeca-1(17),15(18)-dien-10-yl)but-3-en-1-yl)-2-amino-3-methylbutanethioate benzenesulfonate;   (S)-S-((E)-4-((7S,10S)-7-isopropyl-4,4-dimethyl-2,5,8,12-tetraoxo-9-oxa-16-thia-3,6,13,18-tetraazabicyclo[13.2.1]octadeca-1(17),15(18)-dien-10-yl)but-3-en-1-yl)-2-aminopropanethioate oxalate; and   (R)-S-((E)-4-((7S,10S)-7-isopropyl-4,4-dimethyl-2,5,8,12-tetraoxo-9-oxa-16-thia-3,6,13,18-tetraazabicyclo[13.2.1]octadeca-1(17),15(18)-dien-10-yl)but-3-en-1-yl)-2-aminopropanethioate oxalate.   
     
     
         30 . The method according to  claim 28 , wherein the compound is used for preparation of a pharmaceutical composition. 
     
     
         31 . The method according to  claim 29 , wherein the compound is used for preparation of a pharmaceutical composition. 
     
     
         32 . The method according to  claim 30 , wherein the pharmaceutical composition further comprising one or more anti-cancer agents. 
     
     
         33 . The method according to  claim 31 , wherein the pharmaceutical composition further comprising one or more anti-cancer agents. 
     
     
         34 . The method according to  claim 32 , wherein the one or more anti-cancer agents are selected from the group consisting of cyclophosphamide, dacarbazine, cisplatin, methotrexate, mercaptopurine, thioguanine, fluorouracil, cytarabine, vinblastine, paclitaxel, doxorubicin, bleomycin, mitomycin, prednisone, tamoxifen, flutamide, asparaginase, rituximab, trastuzumab, imatinib, retinoic acid, amifostine, camptothecin, topotecan, thalidomide, lenalidomide, a CDK inhibitor, a proteasome inhibitor, and a HDAC inhibitor. 
     
     
         35 . The method according to  claim 33 , wherein the one or more anti-cancer agents are selected from the group consisting of cyclophosphamide, dacarbazine, cisplatin, methotrexate, mercaptopurine, thioguanine, fluorouracil, cytarabine, vinblastine, paclitaxel, doxorubicin, bleomycin, mitomycin, prednisone, tamoxifen, flutamide, asparaginase, rituximab, trastuzumab, imatinib, retinoic acid, amifostine, camptothecin, topotecan, thalidomide, lenalidomide, a CDK inhibitor, a proteasome inhibitor, and a HDAC inhibitor. 
     
     
         36 . The method according to  claim 30 , wherein the pharmaceutical composition is administered for treating a disease mediated by HDAC enzymes selected from the group consisting of cancers, viral diseases, inflammatory diseases, auto immune diseases, allergic diseases and diseases of the central nervous systems. 
     
     
         37 . The method according to  claim 31 , wherein the pharmaceutical composition is administered for treating a disease mediated by HDAC enzymes selected from the group consisting of cancers, viral diseases, inflammatory diseases, auto immune diseases, allergic diseases and diseases of the central nervous systems.